The BH3-only Bcl-2 family protein PUMA (p53 upregulated modulator of apoptosis; also referred to as Bbc-3: Bcl-2 binding component-3) can bind the antiapoptotic Bcl-2 protein and facilitate the expression, conformational change, and mitochondrial translocation of Bax leading to apoptosis. PUMA has been reported to transmit p53-dependent apoptotic signals induced by DNA damage, hypoxia, or oncogenes. In addition, cytokine withdrawal, glucocorticoids, kinase inhibitors, and phorbol esters have also been shown to cause apoptosis through PUMA expression without involving p53. Recently, p73 emerged as another transcription factor eliciting apoptosis by PUMA-mediated Bax mitochondrial translocation.
Cell death in the form of necrosis as well as apoptosis mainly accounts for cardiac contractile dysfunction upon ischemia/reperfusion. Although p53 overexpression can induce cell death in most cell types, the role of endogenous p53 in postischemic cardiac myocyte death remains controversial. On the other hand, Bax-ablation as well as cardiac Bcl-2 or Bcl-xL overexpression has been demonstrated to moderately improve tolerance to ischemia/reperfusion injury. Since PUMA is expressed in response to various stimuli through p53, p73, and other, yet unknown transcription factors and seems to act upstream of Bax, endogenous PUMA activation may significantly contribute to ischemia/reperfusion-induced cardiomyocyte death (FIG. 1).